Alzheimer's disease is a disease in which mature neurons die followed by synaptopathy. Owing to the recent research, it is becoming known that the onset of Alzheimer's disease takes place in stages. In a first stage, synaptopathy mainly occurs. This stage is a reversible stage. In a subsequent stage of the reversible stage, neurons die. This stage is an irreversible stage, and it is considered that the onset of Alzheimer's disease takes place when the irreversible stage is reached (Noguchi et al. J. Biol. Chem. vol. 284 no. 47 32895-32905 (2009)).
It is considered that synaptopathy occurs mainly when accumulated β amyloid (Aβ) dimer and dodecamer act on a glutamic acid receptor or the like. However, none of the Aβ dimer and dodecamer causes death of neurons in vitro and in vivo (Shankar et al. Nature Medicine 14, 837-842 (2008)). Therefore, in order to analyze a clinical condition of human Alzheimer's disease, it is necessary to clarify a cause of death of neurons occurring in the irreversible stage after the reversible synaptopathy stage and an underlying molecular mechanism.
Amylospheroid (ASPD) is a unique Aβ assembly that does not exhibit toxicity to non-neuronal cells or immature neurons and that selectively causes death of functionally mature neurons (Noguchi et al. J. Biol. Chem. vol. 284 no. 47 32895-32905 (2009)). Amylospheroid was first isolated as a spherical Aβ assembly having a diameter of about 10 nm causing death of neurons in vitro (Hoshi et al. Pro. Nat'l. Acad. Sci. U.S.A. vol. 100, no. 11, 6370-6375 (2003)). After that, antibodies specific to the synthetic amylospheroid were produced (WO2006/016644 and WO2009/057664), and amylospheroid formed in a living body from the brain of a human patient suffering from Alzheimer's disease (that is, native amylospheroid) was isolated through use of the antibodies (Hoshi et al. Pro. Nat'l. Acad. Sci. U.S.A. vol. 100, no. 11, 6370-6375 (2003)). It was clarified from the research using the native amylospheroid that i) the native amylospheroid selectively induces death of cells with respect to mature neurons in the same way as in the synthetic amylospheroid, ii) the amount of the native amylospheroid in the cerebral cortex of an Alzheimer's disease patient in which neuronal loss is recognized increases relative to the severity of Alzheimer's disease, and in the cerebellum of an Alzheimer's disease patient in which neuronal loss is not so recognized, the native amylospheroid is present merely in a small amount (Hoshi et al. Pro. Nat'l. Acad. Sci. U.S.A. vol. 100, no. 11, 6370-6375 (2003)). Thus, it is considered that amylospheroid plays an important role in the irreversible stage in which the onset of Alzheimer's disease takes place. Further, the native amylospheroid also was detected from the brain of a patient suffering from dementia with Lewy bodies (Noguchi et al. J. Biol. Chem. vol. 284 no. 47 32895-32905 (2009)), and hence, amylospheroid is also considered to play an important role in the onset of dementia with Lewy bodies.
It has been pointed out that amylospheroid, and Aβ dimer and dodecamer which are considered as main causes for synaptopathy, are formed from an Aβ monomer through different paths although they are both Aβ assemblies. That is, the Aβ dimer and dodecamer are formed via the Aβ dimer, whereas amylospheroid is formed from an Aβ trimer (Matsumura et al. J. Biol. Chem. vol. 286 no. 13, 11555-11562 (2011)).
It was predicted that, unlike other Aβ assemblies, amylospheroid binds to the surface of presynaptic cells to induce death of cells with respect to mature neurons (Noguchi et al. J. Biol. Chem. vol. 284 no. 47 32895-32905 (2009)). However, how amylospheroid binds to the mature neurons has remained unclear.